The goal of our research is to translate the advances in genetics into clinical applications and develop novel neuroprotective therapies for Parkinson's disease (PD) targeted on appropriate genotypes for optimal safety and efficacy. PD is a progressive movement disorder that affects 1-2% of the population over the age of 60, and many who are younger. The prevalence of PD is expected to double in the next 20 years and continue to rise with the aging of the population. Symptomatic treatment is available, but progression of disease and complications of therapy cause increasing disability. Presently, there is neither a cure nor an effective treatment that can prevent the disease or delay its onset. Clinical neuroprotective trials have not been successful. PD susceptibility is determined by cumulative and interactive effects of genes and environmental factors; therefore, protection against PD may be possible if the right neuroprotective therapy is targeted on the specific genotypes that promote their beneficial effects. Nicotine and caffeine are neuroprotective in animal models and are robustly associated with reduced risk of PD in humans. We propose to identify the genes that enhance or diminish the effects of smoking/nicotine and caffeine. The genes will in turn become targets for drug development, markers for subdividing patients in clinical trials, and a basis for individualized therapy. We have planned a novel integrated approach, using Drosophila for its powerful genetic techniques and NeuroGenetics Research Consortium (NGRC) for its large well-characterized patient population. The human studies in itself will be comprehensive and include hypothesis-neutral genome-wide studies and hypothesis- driven candidate gene and pathway analyses. The following experiments will be performed: (1) a genome- wide gene-environment interaction study, (2) deficiency screening in the paraquat Drosophila model to identify loci that modify rescue by nicotine and caffeine, and testing the human homologues in NGRC cases and controls, (3) testing human candidate genes and regulatory regions in pathways of interest for their effect on smoking- or coffee-associated PD risk reduction, (4) replication in independent studies. Through these complementary studies, we aim to identify and confirm genetic loci that affect risk of PD through interaction with smoking or coffee, to form the basis for development of predictive markers and therapeutic targets.